3A,12B-DIHYDRO-8H-DIBENZO{8 3,4,6,7{9 CYCLOHEPT{8 1,2-d{9 OXAZOL-8-ONES

ABSTRACT

3a,12b-dihydro-8H-dibenzo( 3,4,6,7) cyclohept( 1,2,-d) oxazol-8ones having at the 2-position an alkylated amino group and 2,3,3a,12b-tetrahydro-8H-dibenzo( 3,4,6,7) cyclohept( 1,2-d) oxazol-8-ones having at the 2-position an alkylated imino group are prepared, inter alia, by reacting a corresponding dibenzocyclohept-oxazole compound having at the 2-position an unsubstituted amino, an alkyl substituted mercapto, an unsubstituted imino or a thioxo group, with an appropriate amine. The compounds of the invention are useful, for example, as antidepressant agents.

United States Patent lnventors Albrecht Edenhofer Riehen; HansSpiegelberg, Basel, both of Switzerland Appl. No. 714,320

Filed Mar. 19, 1968 Patented Dec. 7, 1971 Assignee Hoffmann-La RocheInc. Nutley, NJ.

Priority Mar. 23, 1967 Switzerland 4246/673A,12B-DlHYDRO-8H-DIBENZO[3,4,6,7] CYCLOHEPT[ l ,Z-DJOXAZOL-S-ONES 20Claims, No Drawings [1.8. U ..260/247.5 R, 260/247. 1 260/247.2 R,260/268 PC, 260/293 R, 260/293.4 A, 260/293.4 C, 260/294.7 C,

Int. Cl C07d 99/00 [50] Field oi Search 260/307.4. 247.5 R, 268 PC,293.4 A 307.1. 294.7 C

[56] References Cited UNITED STATES PATENTS 3,478,048 I l/l969 Edenhoferet al. 260/307.4

Primary Examiner--Nicholas S. Rizzo Assistant Examiner-Anne Marie T.Tighe Attorneys-Samuel L. Welt, Jon S. Saxe, William H. Epstein, GeraldS. Rosen, Bernard S. Leon and William G. lsgro ABSTRACT:3a,l2b-dihydro-8H-dibenzo[3,4,6,7]cyclohept[ l,2,-d]0xazol-8-ones havingat the 2-position an alkylated amino group and2,3,3a,lZb-tetrahydro-SH-dibenzo[3,4,6,7] cyclohept[ l,2-d]oxazol-8-oneshaving at the 2-position an alkylated imino group are prepared, interalia, by reacting a corresponding dibenzo-cyclohept-oxazolle compoundhaving at the 2-position an unsubstituted amino. an alkyl substitutedmercapto, an unsubstituted imino or a thioxo group, with an appropriateamine. The compounds of the invention are useful, for example, asantidepressant agents.

3A. I 2B-DIHYDRO-8H-D1BENZO[3,4,6,7]CYCLOHEPT 1 ,Z-DJOXAZOL-B-ONES BRIEFDESCRIPTION OF THE INVENTION The invention relates todibenzocycloheptene compounds of the formula and wherein R, is hydrogenor alkyl, R is alkyl, alkenyl or cycloalkyl; R and R taken together withthe nitrogen atom are a heterocyclic residue; R is hydrogen, alkyl,alkenyl or cycloalkyl; and R is hydrogen, halogen, alkyl,trifluoromethyl or acyl, as well as the corresponding ketals and thepharmaceutically acceptable acid addition salts thereof. The compoundsof formula I and II are useful antidepressant agents.

DETAILED DESCRIPTION OF THE INVENTION The invention relates todibenzocycloheptenes of the formulas:

wherein R is hydrogen or alkyl; R is alkyl, alkenyl or cycloalkyl; R andR taken together with the nitrogen atom are a heterocyclic residue; R ishydrogen, alkyl, alkenyl or cycloalkyl; and R, is hydrogen, halogen,alkyl, trifluoromethyl or acyl, as well as the corresponding ketals andthe pharmaceutically acceptable acid addition salts thereof.

As used herein, the term alkyl" is to be understood preferably to mean astraight or branched chain lower alkyl group of one to seven carbonatoms, such a methyl, ethyl, isopropyl, butyl, pentyl, heptyl and thelike. The term alkenyl is to be understood to mean preferably a straightor branched lower alkenyl group having from two to seven carbon atomssuch as allyl, butenyl, hexenyl and the like. The term cycloalkyl is tobe understood to mean unsubstituted or lower alkyl substitutedcycloalkyl of three to 12 carbon atoms, preferably three to six carbonatoms, such as, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Theterm fhalogen" includes chlorine, bromine, fluorine and iodine,preferably chloride and bromine. The term acyl is to be understood tomean preferably alkanoyl or alkylsulfonyl of one to seven carbon atomssuch as acetyl, methyl sulfonyl and the like. The term heterocyclicresidue" is to be understood to mean a five or six member heterocyclicresidue such as piperidyl, piperazinyl or morpholinyl.

Compounds of this invention corresponding to formula I are exemplifiedby the following:

2-(Methylamino)-3a,l2b-dihydro8H -dibenzo [3,4,6,7 ]cycloheptl,2-d]oxazol-8-one;

2- (Ethylamino)-3a, l 2b-dihydro-8H -dibenzo [3,4,6,7,]cyclohept[l,2-d]oxazol-8-one;

2-(Butylamino)-3a,12b-dihydro-8I-I-dibenzo[3,4,6,7]cyclohept[l,2-d]oxazol-ne;

2-( Allylamino )-3a, 1 2b-dihydro-8li-I- dibenzo [3,4,6,7]cyclohept[l,2-d]oxazol-8-one;

2-( Cyclopropylamino)-3a, l 2b-dihydro-8H -dibenzo[3,4,6,7 ]cyclohept[ l,2-d]oxazol-8-one;

2-( Propylamino)-3a, l Zb-dihydroJBH -dibenzo[3,4,6,7]cyclohept[l,2-d]oxazol-8-one;

2-( Dimethylamino)-3a, l 2b-dihydro-8I-I -dibenzo[3,4,6,7 ]cyclohept[ l,2-dloxazol-8one;

2-( Morpholinyl)-3a, l 2b-dihydro-8I-I-dibenzo [3,4,6,7]cyclohept[ l,2-d]oxazol-8-one; and the like.

Compounds of this invention corresponding to formula II are exemplifiedby the following:

2-( Methylimino-2,3 ,3a, 1 Zb-tetrahydro-Bmethyl-8H-dibenzo[3,4,6,7]cyclohept[1,2-d]oxazol-8one:

2-( Ethylimino)-2,3,3a,l 2b-tetrahydro-3methyl-8I-I-dibenzo[3,4,6,7]cyclohept[ l,2,-d oxazol-S-one;

2-( Methylimino )-2,3,3a, l 2b-tetrahydro-3cyclopropyl 8H-dibenzo[3,4,6,7 ]cyclohept[ 1 ,2-d]oxazol-8-one;

2-( Methylimino)-2,3,3a, l 2b-tetrahydro-3-isopropyl -8H-dibenzo[3,4,6,7]cyclohept[ l,2-d]oxazol-8-one;

2-(Methylimino-2,3,3a, l 2b-tetrahydro-3-8H-dibenzo[3,4,6,7cyclohept[l,2-d]loxazol-8-one; and the like.

The dibenzocycloheptenes of the invention can be prepared utilizingseveral alternate procedures, for example:

I. A compound of the formula I r AN ms. W (l l} wherein R and R are aspreviously described, A is amino 0r alkyl-substituted mercapto, and B isimino or thioxo, or the corresponding ketal of said compound can bereacted, when R is hydrogen, with an amine of the formula wherein R andR are previously described, or when R is alkyl, alkenyl or cycloalkylwith an amine of the formula H N-R V1] wherein R is as previouslydescribed; or 2. A compound of the formula VII wherein R R and R are aspreviously described, or the corresponding ketal can be cyclized, withthe formation of the oxazolidine ring, and the oxazoles obtained can beN-alkylated, if desired. The compounds of formula I or ll obtained canbe ketalized and/or converted into pharmaceutically acceptable acidaddition salt, if desired.

The optionally ring-substituted compounds of formula III or IV which canbe utilized as starting compounds can be produced from the optionallyring-substituted l0, ll-epoxy- 10,11-dihydro-5H-dibenzo[a,dlcyclohepten-S-ones by amination with ammonia ora monoalkyl-substituted amine.

The IO-hydroxy-l l-aminolor alkylamino] 10,! l-dihydro-SH-dibenzo[a,d]cyclohepten-5-ones obtained, which exist in the transform, may be cyclized by treatment with a cyanogen halide such as, forexample, cyanogen bromide, to yield compounds of formula III or IVwherein A is the amino group, and B is the imino group, or by treatmentwith carbon disulfide to yield compounds of formula III or IV wherein Ais the mercapto group, and B is the thioxo group.

The optionally ring-substituted l0,l l-epoxy-l0,l l-dihydro-5H-dibenzo[a,d]cyclohepten-5-ones are known compounds or can be preparedin an analogous manner as known compounds.

The starting compounds of formula Ill or IV may be reacted with aminesor formula V or VI in a known manner. An excess of the amine isconveniently employed.

Compounds of formula III or IV, wherein A is an amino group and B is animino group, may also be reaminated in the absence of a solvent. Thereaction can be accelerated with slight heating, for example, at about40-60 C. When volatile amines are employed it is preferable to work in aclosed system.

The starting compounds of formula [11 Or lV wherein A is a mercaptogroup and B is a thioxo group may be aminated as set out hereinbefore. Asolvent, preferably an alkanol such as methanol, can be advantageouslyutilized. Also, this amination is advantageously carried out at anelevated temperature, preferably at the boiling temperature of thereaction mixture.

Compounds of formula lll wherein A is an alkylmercapto group may also bereacted with amines of formula V or V] in the manner described above.The corresponding starting compounds of formula Ill can be prepared byalkylation of the mercapto group, for example, by treatment with analkylating agent, such as, methyl iodide.

The optionally ring-substituted compounds of formula Vll used asstarting compounds can be obtained from the aforesaid lO-hydro-ll-aminol 0,l l-dihydro-5l-l-dibenzo[a,b] cyclohepten-S-ones by reactionwith an N-alkyl-, N-aklkenylor N-cycloalkyl-substituted isothiocyanate.The reaction can be carried out at a temperature in the range of roomtemperature and the boiling point of the reaction mixture. The reactantsare advantageously reacted in the presence of an inert solvent,preferably in the presence of an alkanol such as ethanol or an ethersuch as dioxane.

The readily crystallizable thioureas of formula Vll may easily bycyclized with the formation of the oxazolidine ring. This cyclizationcan advantageously be carried out with the aid of a hydrogen sulfidebinding agent, for example, with the aid of an oxidizing agent, forexample, a metal oxide, such as, mercury oxide, lead oxide or the like,or by treatment with an alkylating agent, for example, an alkyl halide,such as methyl iodide or the like, with the cleavage of alkyl mercaptan.Advantageously, the reaction can be carried out in the presence of apolar solvent, such as ethanol. The cyclization proceeds particularlysmoothly at an elevated temperature, preferably at the boilingtemperature of the reaction mixture.

Compounds of formula ll wherein R and R are as previously described andR is hydrogen, can be alkylated with an alkylating agent, for example,an alkyl halide, such as, methyl iodide, under mild conditions in thepresence of a polar solvent. The alkylation proceeds particularlysmoothly at room temperature with an excess of the alkylating agent inthe presence of a strongly polar solvent, such as, dimethylformamide.

The compounds of formulas I and ll, which usually exist in the transform, of which 2-(methylamino)-, 2- (dimethylamino)-, 2-(ethylamino)-,2-(allylamino)- and 2- (cyclopropylamino)-3a, l2b-dihydro-8H-dibenzo[ 3,4,6,7 ]cyclohept[ l,2-d]-oxazol-8-one, 2(4-methyll piperazinyl )-3a, 12b-dihydro-8H-dibenzo[ 3,4,6,7] cyclohept[l,2-d]oxazol-8-one, as well as2-(ethylimino)- 2,3,3a, l 2b-tetrahydro-3methyl-SH-dibenzo[3,4,6,7lcyclohe pt[ l,2-d]oxazol-8-one represent particularly valuablesubstances, can be ketalized in a known manner, for example, by theaction of lower alkanols or glycols, preferably by treatment withmethanol or ethyleneglycol.

The compounds of formulas l and II form acid addition salts withpharmaceutically acceptable inorganic and organic acids; for example,with hydrohalic acids, such as, hydrochloric acid, with other mineralacids, such as, sulfuric acid, phosphoric acid, nitric acid, and withorganic acids, such as, tartaric acid, citric acid, oxalic acid,camphorsulfonic acid, salicylic acid, ascorbic acid, maleic acid,mandelic acid and the like. Preferred salts are the hydrochlorides. Thepharmaceutically acceptable acid addition salts are preferably preparedin an inert solvent by treatment of the free base with the correspondingacid.

The compounds of formulas l and ll, their corresponding ketals, andtheir pharmaceutically acceptable acid addition salts possesspsychopharmacological antidepressant activity and are therefore usefulas psychopharmacological antidepressants. Moreover, the compounds offormulas l and ll, and their salts, possess the advantage of beingdevoid of certain undesirable effects, for instance, they aresubstantially free of anticholinergic activity. Their usefulpsychopharmacological antidepressant activity is demonstrated inwarmblooded animals utilizing standard procedures. For example, groupscomprising 10 mice each are administered the test substance in variableamounts subcutaneously. After 16 hours, they are given subcutaneously 5mg./kg. of 2-hydroxy-2-ethyl- 3-isobutyl-9, l O-dimethoxyll,2,3,4,6,7,-hexahydro-l lbl-lbenzyl[a]quinolizine (substance A), and 30minutes thereafter, they are given intraperitoneally 3.75 mg./kg. ofethanol. A control group of 10 animals is given only ethanol. Theduration of sleep is measured in all animals. The percentage decrease induration in sleep in comparison with the duration of the substance Apotentiated sleep reflects the psychopharmacological antidepressanteffect.

When 2-(dimethylamino)-3a, l 2b-dihydro-8H-dibenzo[3,4,6,7]cyclohept[l,2-dloxazol-8-one which has demonstrated anLD of, for example mg./kg. p.o. in mice, is utilized as the testsubstance at dosages in the range of 10-20 mg./kg. s.c., a corresponding33-52 percent decrease in duration of sleep is produced.

When 2-(ethylimino)-2,3,3a,l2b-tetrahydro-3-methyl-8H-dibenzo[3,4,6,7]cyclohept[l,2d]oxazol-8-one, which has demonstrated anLD of, for example, 350 mg./kg. p.o. in mice, is utilized as the testsubstance at a dose of 20 mg./kg. s.c., a corresponding 45 percentdecrease in duration of sleep is produced.

The substantial absence of anticholinergic effect is demonstrated inrabbits. Pilocarpine is administered to urethane narcotized rabbits andtheir saliva drippings are collected in a measuring cylinder over aperiod of IS minutes. Immediately thereafter, they are given 1,3 or 6mg./kg. i.v. of the substance to be evaluated, and their salivadrippings are collected in a measuring cylinder over a period of 15minutes. The saliva drippings of controls are also collected over twosuccessive periods of 15 minutes each. The anticholinergic effect isreported as the percent inhibition of salivation taken in relation tothe saliva production before the administration of the test substance.When 2-(dimethylamino) -3a, l2b-dihydro-8H- dibenzo [3,4,6,7]cyclohept[I,2-d]oxazol-8-one is administered in the range of l-6 mg./kg. i.v., acorresponding 18 to 38 percent inhibition of salivation is produced.When 2- (methylamino)-3a l2b -dihydro-8H-dibenzo [3,4,6,7] cyclohept[l,2-d1oxazol-8-one is administered at a dose of 3mg./kg. i.v., acorresponding 7 percent inhibition of salivation is produced. These aremuch lower than the inhibition ob tained with standardpsychopharmacological antidepressants such as amitriptyline.

The compounds of formulas l and ll and their pharmaceutically acceptableacid addition salts have effects qualitatively similar to those ofamitriptyline, known for its therapeutic uses and properties. Thus, thecompounds of this invention demonstrate a pattern of activity associatedwith psychopharmacological antidepressants of known efficacy and safety.

The compounds of formulas l and ll can be used as medicaments, forexample, in the form of pharmaceutical preparations which contain themor their salts or ketals in admixture with a pharmaceutical, organic orinorganic inert carrier material suited for eternal or parenteralapplication, such as, for example, water, gelatin, gum arabic, lactose,starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols,and the like. The pharmaceutical preparations can be in solid form, forexample, as tablets, dragees, suppositories, capsules or in liquid form,for example, as solutions, suspensions or emulsions. They may besterilized and may contain additives, such as preserving, stabilizing,wetting or emulsifying agent, salts for varying the osmotic pressure orbuffers. They may also contain other therapeutically valuablesubstances.

A suitable pharmaceutical dosage unit contains from about 0.1 to mg. ofacompound of formula l or ll or an equivalent amount of apharmaceutically acceptable acid addition salt thereof. Suitable oraldosage regimens in warm-blooded mammals comprise from about 0.1 mgJkg.per day to about 5 mg./kg. per day. Suitable parenteral dosage regimensin warmblooded mammals comprise from about 0.05 mg./kg. per day to about2.5 mg./kg. per day. However, for any particular subject, the specificdosage regimen should be adjusted according to individual need and theprofessional judgement of the person administering or supervising theadministration of a compound of formula I or ll. It is to be understoodthat the dosages set forth herein are exemplary only and that they donot, to any extent, limit the scope or practice of this invention.

The following nonlimiting examples further illustrate the invention. Alltemperatures are in degrees centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of racemic trans-2-(2-methylamino)-3a,l2bdihydro-8l1l-dibenzo[3,4,6,7 ]cyclohept[ l,2-d]oxazol-8-one 3 g.of racemic trans-2-amino3a,l2b-dihydro8H dibenzo[3,4,6,7]cyclohept[l,2-d]oxazol -8-one were treated with 40 ml. of a 20 percent w/vsolution of methylarnine in ethanol and heated at 90 C. in a closedsystem under a nitrogen atmosphere at 20 atmospheres gauge pressure for4 hours. The reaction mixture was subsequently evaporated under reducedpressure. The residual racemic trans 2-(2- methyl-amino)-3a,l2b-dihydro-8H-dibenzo[3,4,6,7]cyclohe pt[ l ,2-dloxazol-8-one was takenup in ether and treated with 30 percent methanolic hydrochloric acid upto the congoacidic reaction, whereupon the hydrochloride saltprecipitated. After recrystallization from methanol/ether, the racemictrans-2-( 2-methylamino)-3a, l 2b-dihydro-8H-dibenzo[3,4,6,7]cyclohept[1,2-d loxazol-8-one hydrochloride had amelting point of 250C.

EXAMPLE 2 Preparation of racemic 2-(methylamino)-3a, l2b-dihydro-8H-dibenzo[ 3,4,6,7]cyclohept[ l ,2-d1oxazol-8-one hydrochloride 23.2 g. ofracemic 3-methyl-l(trans-l0,ll -dihydro-llhydroxy-5oxo-5l-ldibenzo[a,d]cyclohepten-l0-y1)-2-thiourea were heated underreflux conditions with intensive stirring for 18 hours together with1000 ml. of absolute ethanol and 116 g. of mercuric oxide. The resultingsolution was subsequently filtered over activated carbon, concentratedto about 200 ml. and treated with 30 percent methanolic hydrochloricacid up to the Congo-acidic reaction. The racemictrans-2-(methylamino)-3a, l2b-dihydro-8H-dibenzo[3,4,6,7]cyclohept[l,2-d]oxazol-8-one hydrochloride which precipitated(crystalline) had a melting point of 250-25 1 C. (dec.).

The racemic 3-methyll -(transl 0,1 l-dihydro-l l-hydroxy- 5-oxo-5H-dibenzo[a,d]cyclohepten-lO-yl)2thiourea employed as the startingcompound was, for example, prepared as follows:

30 g. of racemic trans-lO-hydroxy-l l-amino-l0,l ldihydro-diben2o[a,d]cyclohepten-5-one were dissolved in 600 ml. ofabsolute dioxane. The solution was treated dropwise at 20 C. with asolution containing 10 g. of methyl isothiocyanate in 50 ml. of absolutedioxane with stirring for a period of 12 hours. The racemic3-methyl-l-(trans-l0,lldihydro-ll-hydroxy-5-oxo-5Hdibenzo[a,d]cycloheptenl 0- yl)-2-thiourea whichprecipitated had a melting point of l29-l30C.

By the same procedure as is described in detail in this example, thefollowing compounds were prepared:

Racemic trans-2-(ethylamino)-3a, l 2b-dihydro-8H- dibenzo[3,4,6,7]cyclohept[ l,2-d]oxazol-8-one, having a melting point of l98l99C., the corresponding hydrochloride melting at 239 C. (dec.) [fromracemic 3-ethyl- 1 -(Transl0,l l-dihydro-ll-hydroxy-5-oxy-5l-l-dibenzo[a,d]

cycloheptenl O-yl )-2-thiourea Racemic trans-2-(propylamino)--3a,dibenzo[ 3,4,6,7]cyclohept[l,2-d]oxazol-8-o:ne, having a melting pointof l25l27 C., the corresponding hydrochloride melting at 208-210 C.,(dec.) [from racemic 3-propyll-(transl 0,l l-dihydrol l-hydroxy-S-oxo-5H- dibenzo[a,d]cycloheptenl O-yl )-2-thiourea];

Racemic trans-2-(isopropylamino)-3a, l2b-dihydro-8H- dibenzo[3,4,6,7]cyclohept[l,2-dloxazol-8-one, having a melting point of l74l76C., the corresponding hydrochloride having a melting point of 206207 C.,(dec.) [from racemic 3-isopropyl-l(trans-l0,l l-dihydro l l-hydroxy-5-oxo-5H-dibenzo[a,d]cyclohepten-l0-yl)-2-thiourea]:

Racemic trans-2-(butylamino )-3la, l2b-dihydro-8H- dibenzo[3,4,6,7]cyclohept[l,2-d]oxazol8-one, isolated as the correspondinghydrochloride having a melting point of 2] l C., (dec.) [from racemicl-butyl-3-(transl0,l 1 dihydro-ll-hydroxy-5-oxo-5H-dibenzo[a,d]cycloheptenlO-yl)-2-thiourea];

Racemic trans-2-(allylamino)-3a, l 2b-dihydro-8H-dibenzo[3,4,6,7]cyclohept[l,2-d]oxazol-8-one, having a melting point of l23-l25C., the corresponding hydrochloride having a melting point of 200-20Il(dec.) [from racemic l-allyl-3-(trans-l0,l l-dihydro-ll--hydroxy-5-oxo-5H- dibenzo[a,d ]cycloheptenl O-yl )-2-thiourea].

12b-dihydro-8H- EXAMPLE 3 Preparation of racemictrans-2-(dimethylamino)-3a,l2bdihydro-8H-dibenzo[3,4,6,7]cyclohept[ l,2-d]oxazol-8-one 6.2 g. of racemic trans-2-amino-3a,l2b-dihydro-8H-dibenzo[3,4,6,7]cyclohept[ l,2-d]oxaz-o1 -8one were treated with 120 ml.of a 20 percent w/v solvent of dimethylamine in ethanol and heated at C.in a closed system under a nitrogen atmosphere at 5 atmospheres gaugepressure for 4 hours. The reaction mixture was subsequently evaporatedunder reduced pressure, an the residue was taken up in 2-N hydrochloricacid. The resulting solution was washed with ether, filtered overactivated carbon and made basic by addition of concentrated ammonia. Theracemic trans-2- (dimethylamino)-3a, l 2b-dihydro-8H-dlibenzo[ 3,4,6]]cyclohept[ l ,2-d1oxazol-8-one which precipitated had a melting pointof l58-l59 C., The hydrochloride prepared from the base by treatmentwith 30 percent methanolic hydrochloric acid had a melting point of 238240 C.

The following compound was also prepared by the process described inthis example:

Racemic trans-2-(4-methyll -piperazinyl )-3a, l 2b-dihydro- 8H-H-dibenzo[3,4,6,7]cyclohept[ l,2-d]oxazol-8-one, the correspondinghydrochloride having a melting point of 2l4 C. (dec.) [from racemictrans-2-amino-3a,IZb-dihydro- 8H-dibenzo[3,4,6,7]cyclohept[l,2-d]oxazol-8-one and N-methylpiperazine].

EXAMPLE 4 Preparation of racemictrans-2-(dimethylamino)-3a,l2bdihydro-8H-dibenzo[ 3,4,6,7 ]cyclohept[l,2-d ]oxazol-8-one 5 g. of racemic trans 2,3,3a,l2b-tetrahydro-2Thioxo-8H- dibenzo[3,4,6,7cyclohept[l,2-dloxazol-8-onewere heated under reflux conditions at 63C. under a nitrogen atmospherefor 1 hour with 25 ml. of absolute methanol and 25 ml. of dimethylamine.The reaction mixture was subsequently evaporated, and the residue wastaken up in 2-N hydrochloric acid. The solution was washed with etherand made alkaline by the addition of concentrated ammonia. The racemictrans-2-( 2- dimethylamino)-3a, l2b-dihydro-8H-dibenzo[3,4,6,7]cyclohept[ l,2-d]oxazol-8-one which precipitated was dissolvedin methylene chloride. The resulting solution was dried under sodiumsulfate and evaporated under reduced pressure. After recrystallizationfrom methanol, the base had a melting point of l58l59 C. The base wasdissolved in ether and treated with 30 percent methanolic hydrochloricacid to yield the corresponding hydrochloride having a melting point of238240 C.

The racemic trans- 2,3,3a, 12b-tetrahydro-2-thioxo-8H-dibenzol3,4,6,7cyclohept[ l ,2-d]oxazol 8-one employed as the startingcompound was, for example, prepared as follows:

27.5 g. of racemic trans-lO-hydroxy-l l-amino-l0,l l dihydro'5H-dibenzo[a,d]cyclohepten-5-one, 200 ml. of ethanol and 70 ml. of waterwere brought to a boil. Thereafter, 1 lg. of trithiocarbonate acid werequickly added. After applying strong reflux conditions, the mixture wasallowed to reflux with stirring for 18 hours. Then, 4 ml. ofconcentrated hydrochloric acid were added, and the mixture was reactedfor an additional hour. Thereafter, the reaction mixture was stirred for12 hours in a cool place, and the resulting crystalline precipitate wasremoved by filtration. The crystalline material was washed with aboutlSO ml. of ethanol/water to yield racemictrans-2,3,3a,l2b-tetrahydro-2-thioxo-8H- dibenzo[3,4,6,7]cyclohept[1,2-d]oxazol-8-one having a melting point of 226-229 C.

By the same procedure as is described in detail in this example, thefollowing compounds were prepared:

Racemic trans-2-(4-methyll -piperazinyl )-3a, 1 Zb-dihydro- 8l-l-dibenzo[3,4,6,7]cyclohept[ l ,2-d]oxazol-8-one hydrochloride, havinga melting point of 2l4 C. (dec.) [from racemictrans-2,3,3a,lZb-tetrahydro-2-thioxo-8H-dibenzo[3,4,6,7]cyclohept[l,2-d]oxazol-8-one and N- methylpiperazine];and Racemic trans-2-morpholino-3a, l2b-dihydro-8H-dibenzo [3,4,6,7]

cyclohept[ l ,2-d]oxazol-8-one hydrochloride having a melting point of2l9-220 C. [from racemic trans- 2,3,3a, l2b-tetra-hydro-2-thioxo-8H-dibenzo[3,4,6,7 ]cyclohept[l,2-d]oxazol-8-one and morpholine.

EXAMPLE 5 Preparation of racemictrans-2-(dimethylamino)-3a,l2bdihydro-8H-dibenzo[3,4,6,7]cyclohept[ l,2-d1oxazol-8-one 1.5 g. of racemictrans-3a,lZb-dihydro-2-methylthio-8H-dibenzol3,4,6,7]cyclohept[l,2-d]oxazol-8-one were heated to a boil with130 ml. of ethanol and 20 ml. ofdimethyl sulfoxide, treated dropwisewith stirring with 23 ml. of dimethyl sulfoxide, treated dropwise withstirring with 23 ml. of dimethylamine and l50 ml. ofethanol/dimethylformamide, and stirred at reflux conditions for 18hours. The reaction mixture was subsequently evaporated under reducedpressure and the residue was taken up in 2-N hydrochloride acid. The

resulting solution was washed with ether and made alkaline by theaddition of concentrated ammonia. The racemic trans-2-(dimethylamino)-3a, l 2b-dihydro-8H-dibenzo[ 3,4,6,7' ]cyclohept[1,2-d1oxazol -8-one which precipitated can be converted into thehydrochloride, (which has a melting point of 239 C.) as described inexample 4.

The racemic trans-3a, 1 2b-dihydro-2-methylthio-8H-dibenzol3,4,6,7]cyclohept[l,2-d]oxazol-8-one employed as the startingcompound was, for example, prepared as follows:

2.5 g. of racemic trans-2,3,3a,l2b-tetrahydro-2-thioxo-8H-dibenzo[3,4,6,7]cyclohept[l,2-d]oxazol-8-one were dissolved in 25 ml. of2N sodium hydroxide solution and 25 ml. of ethanol. Thereafter, asolution containing 1 ml. of dimethylsulfate in 10 ml. of ethanol wasadded with rapid stirring. After a short time, a precipitate formed,which was removed by filtration, washed with water and dried underreduced pressure. After recrystallization of the precipitate fromethanol, there was obtained racemic trans-3a, l2b-dihydro-2-methylthio-8H-dibenzo[3,4,6,7]cyclohept[l,2-d]oxazol-8-one having a melting pointof 151 C.

EXAMPLE 6 Preparation of racemic trans-2'-(cyclopropylamino)-3a,l2bdihydro-8H-dibenzo[3,4,6,7]cyclohept[ l ,2-d]oxazol-8-onehydrochloride 0.7 g. of racemic 3-cyclopropyl-l(trans-l0,l l-dihydro-l1- hydroxy 5-oxo-5H-dibenzo[a,d]cyclohepten-lO-yl)-2-thiourea was heatedunder reflux conditions for 5 hours with 10 ml. of ethanol and 0.45 g.of methyl iodide. The reaction mixture was subsequently evaporated todryness under reduced pressure. The residue was moistened with a little3-N ammonium hydroxide and extracted with chloroform. The racemictrans-2- (cyclopropyl-amino)-3a, l 2b-dihydro-8H-dibenzo[ 3 ,4,6,7]cyclohept[ l ,2-d]oxazol-8-one hydrochloride which was prepared fromthe oily base remaining behind after evaporation of the chloroformextract by treatment with methanolic hydrochloric acid, had a meltingpoint of 2l l-2 1 2 C. (dec.) after recrystallization fromethanol/ether.

The racemic 3-cyclopropyl-l-(trans-10,1 l-dihydro-lhydroxy-S-oxo-SH-dibenzo[a,d]cyclohepten-l0-yl)-2-thiourea employed asthe starting compound was, for example, prepared as follows:

4.8 g. of racemic trans-lO-hydroxy-l l-amino-lO,lldihydro-dibenzo[a,b]cyclohepten-5-one were suspended in 200 ml. ofethanol, treated with 2.0 g. of cyclopropyl isothiocyanate and heatedunder reflux conditions for 16 hours. The reaction mixture wassubsequently evaporated under reduced pressure, and the residue wastreated with 10 ml. of 0.lN hydrochloric acid. The crude racemic3-cyclopropyl-l-(transl O, l l -dihydroll-hydroxy-5-oxo-5H-dibenzo[a,d]cyclopheptan-l0-yl)-2-thiourea had amelting point of 207 C. after recrystallization from methanol.

EXAMPLE 7 Preparation of racemic trans-2-(methylimino)-2,3,3a,l2btetra-hydro-3-methyl -8Hdibenzo[3,4,6,7]cyclohept[ l,2- dloxazol-8-onehydrochloride 1.6 g. of racemic l-(trans-l0,l l-dihydro-ll-hydroxy-S-oxo- 5H-dibenzo[a,d ]cycloheptenl O-yl l,3-dimethyl-2-thiourea were heated under reflux conditions for 12 hourswith 50 ml. of ethyl alcohol and 1.0 g. of methyl iodide. The reactionmixture was subsequently evaporated under reduced pressure and theresidue was taken up in chloroform. The chloroform extract was washedwith aqueous ammonia, dried over potassium carbonate and evaporatedunder reduced pressure. The racemictrans-2(methylimino)-2,3,3a,l2b-tetrahydro-3- methyl-8H-dibenzo[3,4,6,7]cyclohept[ l,2-d]oxazol-8-one hydrochloride preparedfrom the residual oily base by treatment with methanolic hydrochloricacid had a melting point of 248-249 C. (dec.) after reprecipitation fromabsolute ethanol/ether.

The racemic l-(transl 0,1 l-dihydro-ll-hydroxy-S-oxo-Sll-lldibenzo[a.d]cyclohepten-lOyl)-2,3-dimethyl-2-thioureaemployed as starting compound was, for example, prepared as follows:

2.5 g. of racemic trans-lO-hydroxy-l l-methylamino-l0,lldihydro-dibenzola,d]cyclohepten-5-one were suspended in 70 ml. ofethanol and, after the addition of 0.8 g. of methyl isothiocyanate, themixture was heated under reflux conditions for 6 hours. The racemicl-(trans-l0,l l-dihydro-llhydroxy-5-oxo-5l-l-dibenzo[a,d]cyc1ohepten-l0-yl)-l ,3-dimethyl-Z-thiourea which separates out (crystalline) upon cooling thereaction mixture had a melting point of 225 C. (dec.) afterrecrystallization from ethanol.

By the same procedure as is described in detail in this example, thefollowing compounds were prepared:

Racemic trans-2-( methylimino )-2,3,3a, l 2b-tetrahydro-3 hydrochloride,having a melting point of 235-236 C. (dec.) [from racemicl-ethyl-l-(trans- 10,1 l-dihydro-l lhydroxy5-oxo-5l-l-dibenzo[a,d]cycloheptenl -yl )-3- methyl-Z-thiourea];

Racemic trans-2'(ethylimino)-2,3,3a, l2b-tetrahydro-3- hydrochloride,having a melting point of 239 C. (dec.) [from racemic l-methyll transl0,1 l-dihydro-l lhydroxy-S -oxo-ll-l-dibenzol a,d ]cycloheptenl O-yl)-3- ethyl-Z-thiourea];

Racemic trans-2-( methylimino )-2,3,3a, l 2b-tetrahydro-3 onehydrochloride, having a melting point of 242 C. (dec.) [from racemicl-isopropyl-l-(trans-l0,l dihydro-ll-hydroxy-5-oxo-5H-dibenzo[a,dlcycloheptenlO'yl)-3-methyl-2-thiourea];and

Racemic trans-2-( methylimino)-2,3,3a, l 2b-tetrahydro-3-cyclopropyl-8l-l-dibenzo[ 3 ,4,6,7]cyclohept[ l ,2-dloxazol- 8-onehydrochloride, having a melting point of 235 C. (dec.) [from racemicl-cyclopropyl-l-(trans-l0,l ldihydro-ll-hydroxy-S-oxo-SH-dibenzo[a,d]cycloheptenl0-yl )-3-methyl-2-thiourea.

EXAMPLE 8 Preparation of racemictrans-2-ethylimino-2,3,3a,l2btetrahydro-3-methyl-8l-l-dibenzo[3,4,6,7]cyclohept[1,2-d]oxazol-l3 one 13g. of racemictrans-2-ethylamino-3a,l2bdihydro-8ll-ldibenzo{3,l,6,7]cyclohept[l,2d]oxazol -8-one, 1.3 g. of methyl iodide and 200 ml. ofdimethylfomlamide were mixed and, with the exclusion of light, allowedto stand at room temperature for 5 days. The reaction mixture formed aclear yellow solution from which the reaction product graduallycrystallizes out. The mixture is evaporated under reduced pressure. Theresidue was taken up in water and extracted with chloroform. Thechloroform phase was discarded. The aqueous phase was made alkaline withl-N caustic soda and exhaustively extracted with chloroform. Thechloroform extracts were washed with water, dried over potassiumcarbonate and evaporated under reduced pressure. The residual racemictrans-2-ethylimino-2,3,3a, l 2b-tetrahydro3-methyl-Sll-l-dibenzo[3,4,6,7]cyclohept[ l,2-d]oxazol-8-one was taken up inether and treated with 30 percent methanolic hydrochloric acid up to thecongo-acidic reaction. The racemic trans-2- ethylimino-2,3,3a, l2b-tetrahydro-3-methyl-8H-dibenzo[ 3,4,6,7]cyclohept[l,2-d]oxazol-8'onehydrochloride which precipitated had a melting point of 236-237 C.(dec.) after recrystallization from ethanol/ether.

EXAM lPLE 9 Capsule Formulation Racemic trans-Z4dimetl'lylamino)-3a.l2b- Per (.apsule dihydro-8H-dibenzo[3,4,6,7]cyclochloride )9 mg. Wmannitol 110 mg. talcum 5 mg.

ill

EXAMPLE 10 Dragees Formulation Racemic lruns2-(ethylumino)-3a.lZb-dihydroilH-dibenzo 13.4.6.7]cyclohcpt 1.2-d]

oxnzol-S-one hydrochloride 25 mg.

mannitol I00 mg.

corn starch 20 mg.

tulcum 5 mg.

The active substance mixed with the mannitol and passed through a No. 5sieve (mesh width about 0.23 mm.). A 10 percent aqueous paste isprepared from the corn starch and homogeneously mixed with the activesubstance mixed with the mannitol. The moist mass is passed through aNo. 3 sieve (mesh width about 1.0 mm.). The granulatc is dried and,after addition of the talcum, is pressed into biconvex kernels having aweight of 150 mg. The kernels can be coated in the usual manner bydredging with a sugar layer.

We claim:

11. A compound of the formula wherein R, is selected from the groupconsisting of hydrogen and lower alkyl of one to seven carbon atoms; Ris selected from the group consisting of lower alkyl of one to sevencarbon atoms, lower alkenyl of two to seven carbon atoms and lowercycloalkyl of three to six carbon atoms; R and R taken together with thenitrogen are piperidyl, piperazinyl, 4-methylpiperazinyl or morpholinyl;and R is selected from the group consisting of hydrogen, halogen, loweralkyl of one to seven carbon atoms, trifluoromethyl, alkanoyl of one toseven carbon atoms, trifluoromethyl, alkanoyl of one to seven carbonatoms and alkyl-sulfonyl of one to seven carbon atoms, its ketals andpharmaceutically acceptable acid addition salts.

2. A compound according to claim 11, wherein R and R are hydrogen.

3. A compound according to claim 2, which is the trans stereoisomer.

4. A compound according to claim 3, wherein R is lower alkyl of one toseven carbon atoms.

5. A compound according to claim 4, wherein R is methyl, i.e.,2-(methylamino)-3a,l2b-dihydro-8H dibenzo[3,4,6,'7 )cyclohept[ l,2-d1oxazol-8-one.

6. A compound according to claim 4, wherein R is ethyl, i.e.,2-(ethylainino)-3a, l 2b-dihydro-8H-dibenzo[3 ,4,6,7 ]cyclohept[ 1,2-dloxazol-S-one.

'7. A compound according to claim 4, wherein R is butyl, i.e.,2-(butylamino)-3a,l2b-dihydro-8H-dibenzo[3,4,6,7

8. A compound according to claim 4', wherein R is propyl, i.e.,2-(propylamino)-3a,l2b-dihydro-8l-l-dibenzo[3,4,6,7 ]cyclohept[ 1,2-d]oxazol-8-one.

9. A compound according to claim 4, wherein R, is isopropyl, i.e.,dibenzo[3,4,6,7]cyclohept[ l ,2-dloxazol-8-one.

10. A compound according to claim 4, wherein R, is lower alkenyl of twoto seven carbon atoms.

11. A compound according to claim 10, wherein R, is allyl, i.e. 2(allylamino )-3a, 1 2b-dihydro-8H-dibenzo[ 3,4,6,7 ]cycloheptl ,2-d]oxazol-8-one.

12. A compound according to claim 3, wherein R, is lower cycloalkyl ofthree to six carbon atoms.

13. A compound according to claim 12, wherein R, is cyclopropyl, i.e.,2(Cyclopropylamino)-3a,l2b-dihydro-8H- dibenzo[ 3,4,6,7]cyclohept[ l,2-d]oxazol-8-one.

14. A compound according to claim 4, wherein R and 2 together with thenitrogen are piperidyl, piperazinyl, 4- methyl-piperazinyl ormorpholinyl.

2-( isopropylamino)-3a, l Zb-dihydro-SH- 15. A compound according toclaim 14, 2-(4-methyl-lpiperazinyl )-3a, 1 2b-dihydro-8H-dibenzo[3,4,6,7] cyclohept[ l ,2-d1oxazol-8-one.

16. A compound according to claim 14, 2-(morpholinyl)-3a,12b-dihydro-8H-dibenzol3,4,6,7]cyclohept[ l,2-d ]oxazol- 8-one.

17. A compound according to claim 1, wherein R is lower alkyl of one toseven carbon atoms.

18. A compound according to claim 17, which is the trans stereoisomer.

19. A compound according to claim 18, wherein R, is lower alkyl of oneto seven carbon atoms.

20. A compound according to claim 19, wherein R and R, are methyl, i.e.,2-(diemthylamino)-3a,l2b-dihydro-8H- dibenzo[3,4,6,7]cyclohept[l,2-d]oxazol-8-one.

2. A compound according to claim 1, wherein R1 and R4 are hydrogen.
 3. Acompound according to claim 2, which is the trans stereoisomer.
 4. Acompound according to claim 3, wherein R2 is lower alkyl of one to sevencarbon atoms.
 5. A compound according to claim 4, wherein R2 is methyl,i.e., 2-(methylamino)-3a,12b-dihydro-8H-dibenzo( 3,4,6,7)cyclohept( 1,2-d)oxazol-8-one.
 6. A compound according to claim 4, wherein R2 isethyl, i.e., 2-(ethylamino)-3a,12b-dihydro-8H-dibenzo(3,4,6,7)cyclohept-(1,2-d)oxazol-8-one.
 7. A compound according to claim4, wherein R2 is butyl, i.e., 2-(butylamino)-3a,12b-dihydro-8H-dibenzo(3,4,6,7)cyclohept( 1,2-d)oxazol-8-one.
 8. A compound according to claim4, wherein R2 is propyl, i.e.,2-(propylamino)-3a,12b-dihydro-8H-dibenzo( 3,4,6,7)cyclohept( 1,2-d)oxazol-8-one.
 9. A compound according to claim 4, wherein R2 isisopropyl, i.e., 2-(isopropylamino)-3a,12b-dihydro-8H-dibenzo( 3,4,6,7)cyclohept( 1,2-d)oxazol-8-one.
 10. A compound according to claim 4,wherein R2 is lower alkenyl of two to seven carbon atoms.
 11. A compoundaccording to claim 10, wherein R2 is allyl, i.e.,2-(allylamino)-3a,12b-dihydro-8H-dibenzo( 3,4,6,7)cyclohept(1,2-d)oxazol-8-one.
 12. A compound according to claim 3, wherein R2 islower cycloalkyl of three to six carbon atoms.
 13. A compound accordingto claim 12, wherein R2 is cyclopropyl, i.e.,2-(cyclopropylamino)-3a,12b-dihydro-8H-dibenzo( 3,4,6, 7)cyclohept(1,2-d)oxazol-8-one.
 14. A compound according to claim 4, wherein R1 andR2 together with the nitrogen are piperidyl, piperazinyl,4-methyl-piperazinyl or morpholinyl.
 15. A compound according to claim14, 2-(4-methyl-1-piperazinyl)-3a,12b-dihydro-8H-dibenzo(3,4,6,7)cyclohept( 1,2-d)oxazol-8-one.
 16. A compound according to claim14, 2-(morpholinyl)-3a,12b-dihydro-8H-dibenzo( 3,4,6,7)cyclohept(1,2-d)oxazol-8-one.
 17. A compound according to claim 1, wherein R1 islower alkyl of one to seven carbon atoms.
 18. A compound according toclaim 17, which is the trans stereoisomer.
 19. A compound according toclaim 18, wherein R2 is lower alkyl of one to seven carbon atoms.
 20. Acompound according to claim 19, wherein R1 and R2 are methyl, i.e.,2-(dimethylamino)-3a,12b-dihydro-8H-dibenzo( 3,4,6, 7)cyclohept(1,2-d)oxazol-8-one.